3'-O-Acetylhamaudol

Structure-activity Relationship Studies on VEGFR2 Tyrosine Kinase Inhibitors for Identification of Potential Natural Anticancer Compounds.[Pubmed:38299297]

Med Chem. 2024 Jan 29.

BACKGROUND: Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved many drugs that show adverse effects, such as hypertension, hypothyroidism, etc. There is a need to discover potent natural compounds that show minimal side effects. In the present study, we have taken structurally diverse known VEGFR2 inhibitors to develop a Quantitative Structure-Activity Relationship (QSAR) model and used this model to predict the inhibitory activity of natural compounds for VEGFR2. METHODS: The QSAR model was developed through the forward stepwise Multiple Linear Regression (MLR) method. A developed QSAR model was used to predict the inhibitory activity of natural compounds. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment and molecular docking studies were performed. The binding stability of the natural compounds with VEGFR2 was elucidated through Molecular Dynamics (MD) simulation. RESULTS: The developed QSAR model against VEGFR2 showed the regression coefficient of the training dataset (r2) as 0.81 and the external regression coefficient of the test dataset (r2 test) 0.71. Descriptors, viz., electro-topological state of potential hydrogen bonds (maxHBint2, nHBint6), atom types (minssNH), maximum topological distance matrix (SpMAD_Dt), and 2D autocorrelation (ATSC7v), have been identified. Using this model, 14 natural compounds have been selected that have shown inhibitory activity for VEGFR2, of which six natural compounds have been found to possess a strong binding affinity with VEGFR2. In MD simulation, four complexes have shown binding stability up to 50ns. CONCLUSION: The developed QSAR model has identified 5 conserved activity-inducing physiochemical properties, which have been found to be correlated with the anticancer activity of the nonidentical ligand molecules bound with the VEGFR2 kinase. Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin have been obtained as possible lead natural compounds against the VEGFR2 kinase.

Saposhnikovia divaricata root and its major components ameliorate inflammation and altered gut microbial diversity and compositions in DSS-induced colitis.[Pubmed:38024289]

Integr Med Res. 2023 Dec;12(4):100998.

BACKGROUND: The root of Saposhnikovia divaricata (Turcz.) Schischk is a well-known traditional medicinal plant, containing various bioactive compounds with anti-inflammatory, antioxidant, and analgesic properties. However, no scientific studies have validated its clinical use as an anti-inflammatory agent against inflammatory bowel disease (IBD). This study aimed to investigate whether the root extract of S. divaricata ameliorates IBD and induces gut microbial alteration, using a RAW 264.7 cell line and a DSS-induced colitis mouse model. METHODS: To investigate the anti-inflammatory effects and alleviation of IBD, using a methanol extract of Saposhnikovia divaricata (Turcz.) Schischk. root (MESD), RAW 264.7, murine macrophages and a dextran sodium sulfate (DSS)-induced colitis mouse model were employed. 16S rRNA gene sequencing was conducted to determine the alterations in the gut microbiota of mice with DSS-induced colitis. RESULTS: MESD significantly decreased nitric oxide (NO) and inflammatory cytokine levels in lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro. Oral administration of MESD reduced the expression of inflammatory cytokines in the colons of mice with DSS-induced colitis. Additionally, MESD inhibited the abundance of Clostridium sensu stricto 1 and enhanced the predicted functional pathways, including l-glutamate degradation VIII (to propanoic acid). Seven compounds with anti-inflammatory properties were isolated from the MESD. Among them, 3'-O-acetylhamaudol and 3'-O-angeloylhamaudol exhibited strong anti-inflammatory effects in vitro. CONCLUSION: Overall, MESD may be a potential natural product for the treatment of IBD by lowering inflammatory cytokine levels and altering gut microbiota composition.

Bioactivity-guided isolation of trypanocidal coumarins and dihydro-pyranochromones from selected Apiaceae plant species.[Pubmed:37331573]

Phytochemistry. 2023 Sep;213:113770.

Bioactivity-guided isolation of natural products from plant matrices is widely used in drug discovery. Here, this strategy was applied to identify trypanocidal coumarins effective against the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease (American trypanosomiasis). Previously, phylogenetic relationships of trypanocidal activity revealed a coumarin-associated antichagasic hotspot in the Apiaceae. In continuation, a total of 35 ethyl acetate extracts of different Apiaceae species were profiled for selective cytotoxicity against T. cruzi epimastigotes over host CHO-K1 and RAW264.7 cells at 10 mug/mL. A flow cytometry-based T. cruzi trypomastigote cellular infection assay was employed to measure toxicity against the intracellular amastigote stage. Among the tested extracts, Seseli andronakii aerial parts, Portenschlagiella ramosissima and Angelica archangelica subsp. litoralis roots exhibited selective trypanocidal activity and were subjected to bioactivity-guided fractionation and isolation by countercurrent chromatography. The khellactone ester isosamidin isolated from the aerial parts of S. andronakii emerged as a selective trypanocidal molecule (selectivity index approximately 9) and inhibited amastigote replication in CHO-K1 cells, though it was significantly less potent than benznidazole. The khellactone ester praeruptorin B and the linear dihydropyranochromones 3'-O-acetylhamaudol and ledebouriellol isolated from the roots of P. ramosissima were more potent and efficiently inhibited the intracellular amastigote replication at < 10 muM. The furanocoumarins imperatorin, isoimperatorin and phellopterin from A. archangelica inhibited T. cruzi replication in host cells only in combination, indicative of superadditive effects, while alloimperatorin was more active in fractions. Our study reports preliminary structure-activity relationships of trypanocidal coumarins and shows that pyranocoumarins and dihydropyranochromones are potential chemical scaffolds for antichagasic drug discovery.

Simultaneous UHPLC/MS quantitative analysis and comparison of Saposhnikoviae radix constituents in cultivated, wild and commercial products.[Pubmed:33575969]

J Nat Med. 2021 Jun;75(3):499-519.

Differences in the components of the crude drug Saposhnikoviae radix, both wild and cultivated, and the cultivation duration were examined by UHPLC/MS. As a result, there was no significant difference in composition depending on the region in China where the drug was produced. The most abundant components in all samples were prim-O-glucosylcimifugin, 4'-O-glucosyl-5-O-methylvisamminol, 3'-O-acetylhamaudol and cimifugin. The 1 year-old Saposhnikoviae radix cultivated in Japan had a low component content overall. A comparison of components according to root thickness revealed that glycosides, such as prim-O-glucosylcimifugin and 4'-O-glucosyl-5-O-methylvisamminol, were accumulated in thin roots. In a comparison of the components according to the drying temperature, a large difference was observed in the content of glycosides, and a difference was observed depending on the sugar-binding position. According to a metabolome analysis in domestic commercial products by LC/MS, a characteristic component in the cultivated product was found and its content was low in the 1 year-old sample and high in the 2 year-old sample. If the cultivation duration is prolonged up to about 6 years, the contents of the ingredients are close to those of wild products.

[Quantitative analysis of five components in the rhizome of Angelica polymorpha by RP-HPLC under different UV wavelengths].[Pubmed:21174769]

Zhongguo Zhong Yao Za Zhi. 2010 Oct;35(19):2581-4.

A HPLC method was developed for simultaneouly quantitative analyses of aviprin (1), gosferol (2), 3'R-(+)-hamaudol (3), 3'-O-acetylhamaudol (4) and iso-imperatorin (5) in the rhizome of Angelica polymorpha. The analysis was performed at 25 degrees C on an Agilent Eclipse XDB-C18 analytical column (4.6 mm x 250 mm, 5 microm) with the mobile phase of methanol and H2O in gradient elution [55:45 (0 min)-65:35 (25 min)-95:5 (35 min)]. And the flow rate was 1.0 mL min(-1) with the detection wavelengths of 312 nm (1), 306 nm (2), 300 nm (3), 294 nm (4) and 310 nm (5). Consequently, the reqresion equations were Y = 1.81 x 10(3) X + 7.93 x 10(2) (r = 0.9996), Y = 2.49 x 10(3) X - 2.17 x 10(2) (r = 0.9993), Y = 2.02 x 10(3) X - 1.42 x 10(2) (r = 0.9991), Y = 1.57 x 10(3) X - 0.66 x 10(2) (r = 0.999 7), Y = 2.65 x 10(3) X - 1.47 x 10(2) (r = 0.999 6). And the average recoveries were 99.7% (RSD 0.57%), 100.1% (RSD 1.3%), 100.0% (RSD 1.6%), 99.6% (RSD 1.3%), 99.2% (RSD 0.59%), respectively. The precision, repeatability and stability were all consistent with the request of quantitative analysis. The contents of compound 1-5 in A. polymorpha were determined as 0.525%, 0.044%, 0.046%, 0.043%, 0.15%, respectively. Accordingly, this quantitative analysis method is good for the quality control of A. polymorpha.

Anti-tumor actions of major component 3'-O-acetylhamaudol of Angelica japonica roots through dual actions, anti-angiogenesis and intestinal intraepithelial lymphocyte activation.[Pubmed:18358599]

Cancer Lett. 2008 Jun 28;265(1):84-97.

We recently demonstrated that two chalcones isolated from Angelica keiskei roots have anti-tumor and anti-metastatic activities through the inhibition of tumor-induced angiogenesis, but the anti-tumor substances of Angelica japonica roots are unknown. We attempted to clarify the anti-tumor action and its mechanisms of a major component 3'-O-acetylhamaudol isolated from A. japonica roots. We first examined the effects of 3'-O-acetylhamaudol on tumor growth in colon 26-bearing mice. Furthermore, we examined the effects of 3'-O-acetylhamaudol on angiogenic factors (vascular endothelial growth factor receptor-2 (VEGFR-2) phosphorylation in human umbilical vein endothelial cells (HUVECs), and vascular endothelial growth factor (VEGF) production and hypoxia-inducible factor (HIF)-1alpha expression in tumors). 3'-O-Acetylhamaudol (25 and 50 mg/kg, twice daily) inhibited the tumor growth in colon 26-bearing mice. Although 3'-O-acetylhamudol had no effect on the VEGF production and HIF-1alpha in colon 26 cells, it (10 microM) inhibited the VEGF-induced angiogenesis and VEGF-induced VEGFR-2 phosphorylation in HUVECs. 3'-O-Acetylhamaudol has anti-tumor effects mediated through dual mechanisms, i.e., anti-angiogenic actions and the modulation of the immune system in the spleen and small intestine in tumor-bearing mice.

Antiproliferative constituents from umbelliferae plants. V. A new furanocoumarin and falcarindiol furanocoumarin ethers from the root of Angelica japonica.[Pubmed:9987830]

Chem Pharm Bull (Tokyo). 1999 Jan;47(1):96-100.

The CHCl3 extract of the root of Angelica japonica showed high inhibitory activity against human gastric adenocarcinoma (MK-1) cell growth. From this extract, a new furanocoumarin named japoangelone and four furanocoumarin ethers of falcarindiol, named japoangelols A-D, were isolated together with caffeic acid methyl ester, four polyacetylenic compounds (panaxynol, falcarindiol, 8-O-acetylfalcarindiol, and (9Z)-1,9-heptadecadiene-4,6-diyne-3,8,11-triol), eight coumarins (osthol, isoimperatorin, scopoletin, byakangelicin, xanthotoxin, bergapten, oxypeucedanin methanolate, and oxypeucedanin hydrate), and two chromones (3'-O-acetylhamaudol, and hamaudol). The structures of the new isolates were determined based on spectral evidence. The ED50 of isolates against MK-1, HeLa, and B16F10 cell lines are reported.